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Generation and Clinical Application of Gene-Modified Autologous Epidermal Sheets in Netherton Syndrome: Lessons Learned from a Phase 1 Trial

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Wei Li Di, Su M. Lwin, Anastasia Petrova, Catina Bernadis, Farhatullah Syed, Farzin Farzaneh, Dale Moulding, Anna E. Martinez, Neil J. Sebire, Dyanne Rampling, Alex Virasami, Mozheh Zamiri, Wei Wang, Havinder Hara, Tendai Kadiyirire, Alya Abdul-Wahab, Magdalena Martinez-Queipo, John I. Harper, John A. McGrath, Adrian J. Thrasher & 2 more Jemima E. Mellerio, Waseem Qasim

Original languageEnglish
Pages (from-to)1067-1078
Number of pages12
JournalHuman Gene Therapy
Issue number9
Early online date5 Aug 2019
E-pub ahead of print5 Aug 2019
Published17 Sep 2019

King's Authors


Netherton syndrome (NS) is a rare autosomal recessive skin disorder caused by mutations in SPINK5. It is a debilitating condition with notable mortality in the early years of life. There is no curative treatment. We undertook a nonrandomized, open-label, feasibility, and safety study using autologous keratinocytes transduced with a lentiviral vector encoding SPINK5 under the control of the human involucrin promoter. Six NS subjects were recruited, and gene-modified epithelial sheets were successfully generated in three of five subjects. The sheets exhibited expression of correctly sized lympho-epithelial Kazal-type-related inhibitor (LEKTI) protein after modification. One subject was grafted with a 20 cm2 gene-modified graft on the left anterior thigh without any adverse complications and was monitored by serial sampling for 12 months. Recovery within the graft area was compared against an area outside by morphology, proviral copy number and expression of the SPINK5 encoded protein, LEKTI, and its downstream target kallikrein 5, which exhibited transient functional correction. The study confirmed the feasibility of generating lentiviral gene-modified epidermal sheets for inherited skin diseases such as NS, but sustained LEKTI expression is likely to require the identification, targeting, and engraftment of long-lived keratinocyte stem cell populations for durable therapeutic effects. Important learning points for the application of gene-modified epidermal sheets are discussed.

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